PROJECT SUMMARY Langerin-expressing dendritic cell (DC) subsets function as immunological sentinels and either activate or regulate immune responses to pathogens and tumor cells. Their importance in the immune system has been established, for example, by the role of Langerhans cells (LCs) in blocking HIV pathogenesis and the role of langerin+ DCs in mounting effector T cell responses to other pathogens. Langerin+ DCs have unique tissue tropism or distribution: LCs are present in the epithelial layer of the skin and mucosal tissues, such as oral, lung, vaginal and intestinal tissues, while other langerin+ DCs are found in the dermal layer and throughout lymphoid and non-lymphoid tissues at low frequencies. There is a significant gap in our understanding of the mechanisms by which the development of these specialized DC subsets is regulated in a tissue-dependent manner. We hypothesize that vitamin A, retinoic acid, and their receptors are key regulators of the development and tissue tropism of most langerin-expressing DCs, regulating the specialized DCs in a manner similar to their roles in regulating embryo morphogenesis by providing spatial cues to developing precursor cells. The overall goal of this project is to establish the roles of retinoic acid- RAR? axis in the regulation of langerin+ DC populations. To test this hypothesis and attain the defined goal, we will determine the role of RAR? as a transcription factor necessary for tissue-specific development of langerin-expressing DC subsets and will study the function of retinoic acid as a negative regulator to limit ectopic development of langerin-expressing DC subsets. The proposed research will identify fundamental functions of vitamin A metabolites and their receptors in regulating langerin- expressing DC subsets. The outcomes are expected to provide novel information regarding the tissue- specific development of langerin-expressing DC subsets. The outcomes will provide novel ideas to maintain effective immunity and to control inflammatory responses mediated by the specialized DC subsets.